AUTHOR=Aterido Adrià , Cañete Juan D. , Tornero Jesús , Blanco Francisco , Fernández-Gutierrez Benjamín , Pérez Carolina , Alperi-López Mercedes , Olivè Alex , Corominas Héctor , Martínez-Taboada Víctor , González Isidoro , Fernández-Nebro Antonio , Erra Alba , López-Lasanta María , López Corbeto Mireia , Palau Núria , Marsal Sara , Julià Antonio 

TITLE=A Combined Transcriptomic and Genomic Analysis Identifies a Gene Signature Associated With the Response to Anti-TNF Therapy in Rheumatoid Arthritis

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01459

DOI=10.3389/fimmu.2019.01459

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints. Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response. The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA.</p><p><bold>Methods:</bold> We performed a sequential multi-omic analysis integrating different sources of molecular information. First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium. Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy. The clinical response was determined at week 14 using the EULAR criteria. Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level. For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain. The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients. Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses.</p><p><bold>Results:</bold> A total of 149 GCMs were identified in the RA synovium. From these, 13 GCMs were found to be significantly associated with anti-TNF response (<italic>P</italic> &lt; 0.05). At the genetic level, we detected two of the 13 GCMs to be significantly associated with the response to adalimumab (<italic>P</italic> = 0.0015) and infliximab (<italic>P</italic> = 0.021) in the Spain cohort. Using the independent cohort of RA patients, we replicated the association of the GCM associated with the response to adalimumab (<italic>P</italic> = 0.0019). The validated module was found to be significantly enriched for genes involved in the nucleotide metabolism (<italic>P</italic> = 2.41e-5) and epigenetic marks from immune cells, including CD4+ regulatory T cells (<italic>P</italic> = 0.041).</p><p><bold>Conclusions:</bold> These findings show the existence of a drug-specific genetic basis for anti-TNF response, thereby supporting treatment stratification in the search for response biomarkers in RA.</p>